Abnormal responsiveness of nephrogenous cyclic AMP excretion following intravenously administered calcium in normocalcaemic squamous cell cancer patients.

The renal response to calcium infusion was compared in ten normocalcaemic patients with squamous cell cancer and in ten normocalcaemic patients with adenocarcinoma. Both groups were comparable with regard to tumour load, renal function, magnesium and 25-hydroxyvitamin D levels. After injection of 3 mg elementary Ca/kg BW nephrogenous cAMP excretion fell significantly in the group of adenocarcinoma patients (1.74 +/- 1.14 nmol/dl GF vs. 2.81 +/- 1.39 nmol/dl GF; P less than 0.01) and TmPO4/GFR rose significantly at 60 and 120 min. No fall in NcAMP excretion was observed in the group of squamous cell cancer patients (2.18 +/- 0.84 vs. 2.24 +/- 0.84 nmol/dl GF; NS) and TmPO4/GFR remained unchanged. Three of ten patients with squamous cell cancer showed a paradoxical rise in NcAMP excretion following calcium administration. The other seven patients with squamous cell cancer showed a decline in NcAMP excretion (delta NcAMP) which was significantly less than in the ten patients with adenocarcinoma (0.52 +/- 0.16 vs. 1.23 +/- 0.74 nmol/dl GF; P less than 0.05). Increased phosphaturia was observed in three of ten patients with squamous cell cancer after calcium was administered. This also occurred in the presence as well as in the absence of a paradoxical activation of the adenylate cyclase system. It is concluded that the abnormal NcAMP response to calcium-infusion in normocalcaemic squamous cell cancer patients might be due to the presence of a non-suppressible PTH-like substance in these patients.

The effect of age on the renal response to PTH infusion.

The renal responses to PTH infusion were compared in two age groups of healthy subjects. Basal nephrogenous cyclic AMP (NcAMP) was higher (1.68 +/- 0.74 vs. 0.97 +/- 0.50 nmol/dl GF; P less than 0.05) and TmPO4/GFR was lower (0.93 +/- 0.21 vs. 1.16 +/- 0.14 mmol/liter; P less than 0.025) in 10 elderly subjects compared with 12 young adults. Creatinine clearance was decreased in the elderly (84.8 +/- 25.7 vs. 144.7 +/- 43.2 ml/min; P less than 0.005) and serum iPTH tended to be increased (0.15 +/- 0.11 vs. 0.11 +/- 0.03 pmol/liter). Following the infusion of 3 IU bPTH/kg bodyweight, no significant differences in delta NcAMP and delta TmPO4/GFR were seen between the groups. When responses were expressed as percentual change of basal level, elderly subjects showed a % NcAMP of 1831 +/- 1200 which was comparable with 2038 +/- 1503% in young adults. However, the percentual change in TmPO4/GFR was significantly higher in elderly persons (24.2 +/- 11.9 vs. 11.9 +/- 8.0%; P less than 0.01). In young subjects, virtually absent TmPO4/GFR responses were found in 3 cases with a relatively low basal TmPO4/GFR (between 0.92 and 0.98 mmol/liter), but these cases showed normal increases in NcAMP. Elderly subjects retained a considerable delta TmPO4/GFR notwithstanding a basal TmPO4/GFR below 0.92 in seven out of 10 cases. These results confirm the existence of a slight increase in parathyroid activity in the elderly. In addition, they suggest an augmented sensitivity of the renal tubule concerning PO4 reabsorption in elderly subjects. It is speculated that this phenomenon is related to the fall in bone mineral retention in senescence and might reflect a defense mechanism against phosphate overload.

End-organ resistance to PTH infusion in hypercalcaemic and normocalcaemic patients with solid tumours.

Ten hypercalcaemic patients with solid tumours were studied to evaluate the renal response on PTH infusion as assessed by nephrogenous cAMP excretion and maximum tubular re-absorption of phosphate. In addition, 20 normocalcaemic patients, 11 with an adenocarcinoma and 9 with a squamous cell carcinoma, were studied. All cancer patients had moderately extensive disease. Results were compared with those of 9 patients with primary hyperparathyroidism and with 10 elderly controls. All groups studied had comparable renal function, magnesium and 25-hydroxy-vitamin D levels. Comparable results were obtained in patients with an adenocarcinoma and in controls. cAMP response (delta nephrogenous cAMP) was significantly lower in the hypercalcaemic patients with a solid tumour compared with the controls (8.13 +/- 4.68 nmol/100 ml glomerular filtrate vs 29.52 +/- 25.62 nmol/100 ml glomerular filtrate; P less than 0.005). In the group of patients with primary hyperparathyroidism delta nephrogenous cAMP was 13.41 +/- 7.54 nmol/100 ml glomerular filtrate (P less than 0.06 vs controls). The group of patients with a squamous cell cancer showed an intermediate value of 14.83 +/- 10.74 nmol/100 ml glomerular filtrate (P less than 0.025 vs the normocalcaemic adenocarcinoma patients, but NS vs controls). In two hypercalcaemic patients with a solid tumour in whom PTH infusion was repeated after normalization of serum calcium no influence on renal responsiveness was observed. Responses of maximum tubular re-absorption of phosphate were lowest in the group of hypercalcaemic patients with a solid tumour and in the patients with primary hyperparathyroidism compared with controls (0.11 +/- 0.10 vs 0.22 +/- 0.09 mmol/l and 0.09 +/- vs 0.22 +/- 0.09 mmol/l; P less than 0.025 and P less than 0.005, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The renal sensitivity for endogenous parathormone in patients with primary hyperparathyroidism, vitamin D deficiency and renal stones.

Baseline levels and increases in urinary cyclic AMP excretion (UcAMP) and immunoreactive parathormone (iPTH) were studied before and during infusion of EDTA in euparathyroid patients with renal stones (n=11), patients with primary hyperparathyroidism (PHP; n=14) and patients with vitamin D deficiency (n = 12). In all three groups, EDTA evoked a significant rise in iPTH and UcAMP. In patients with PHP and in those with vitamin D deficiency, there was a sufficiently close relationship between increments in iPTH (delta iPTH) and in UcAMP (delta UcAMP) (r = 0.90, P less than 0.001 and r = 0.67, P less than 0.02, respectively) to use this model to assess renal sensitivity for changes to endogenous PTH levels. We quantified sensitivity of the kidney for PTH, by calculating the ratio delta UcAMP/delta TPTH for the three studied groups. The ratio was comparable in patients with renal stones (16.7 +/- 10.3) and PHP (13.8 +/- 4.9, P greater than 0.10), but was significantly increased in patients with vitamin D deficiency (33.2 +/- 17.9; P less than 0.01 versus patients with renal stones and P less than 0.01 versus patients with PHP). Within the group of patients with PHP there was no correlation between baseline serum calcium concentrations and the ratio delta UcAMP/delta TPTH. It is concluded that in patients with vitamin D deficiency, renal sensitivity to PTH is increased compared with patients with PHP and euparathyroid patients with renal stones, perhaps an expression of a teleological useful adaptation of end organ sensitivity.

Decreased renal clearance of digoxin in chronic congestive heart failure.

Renal digoxin clearance was compared in patients suffering from atrial fibrillation with well preserved cardiac function (n = 9; salt intake +/- 170 mmol daily) and patients with chronic congestive heart failure (n = 10; salt intake 50 mmol daily and maintenance treatment with diuretics). There was no difference between the groups concerning digoxin dosage, creatinine clearance, diuresis or sodium excretion in the urine. Digoxin clearance in chronic heart failure proved to be significantly lower than in atrial fibrillation (48 +/- 21 vs 71 +/- 36 ml X min-1, p less than 0.05), and Cdig/Ccreat was similarly reduced at 0.73 +/- 0.15 compared to 1.09 +/- 0.27 (p less than 0.005). Steady state serum digoxin concentration was significantly higher in patients with congestive heart failure (1.44 +/- 0.47 vs 0.87 +/- 0.33 micrograms X 1(-1), p less than 0.01). Chronic congestive heart failure is a state with reduced digoxin clearance by the kidney, which could lead to digoxin intoxication not explicable by overdose, reduced renal function or the effect of interacting drugs.

Changes in nephrogenous cyclic AMP excretion and plasma cyclic AMP following treatment of hyperthyroidism.

Plasma cyclic AMP (PcAMP) concentration and the excretion of cyclic AMP/dl GF were estimated in 11 thyrotoxic patients before and after medical treatment. PcAMP concentrations were significantly higher during hyperthyroidism (2.30 +/- 0.69 vs 1.88 +/- 0.71 nmol/dl; P less than 0.05), and total urinary cyclic AMP (TcAMP) excretion showed no significant changes (3.24 +/- 0.64 vs 3.44 +/- 1.77 nmol/dl GF). Nephrogenous (NcAMP) excretion rose significantly (1.00 +/- 0.82 vs 1.68 +/- 1.31 mmol/dl GF; P less than 0.025). The increase in NcAMP excretion correlated significantly with the decrease in serum T3 levels (r = -0.46; P less than 0.05). Serum iPTH levels showed no significant change. Both the serum Ca, corrected for serum total protein and TmPO4/GFR declined after treatment (respectively 2.44 +/- 0.13 vs 2.33 +/- 0.08 mmol/l; P less than 0.05 and 1.18 +/- 0.29 vs 1.05 +/- 0.22 mmol/l; P less than 0.05). It is concluded that the rise in NcAMP excretion corroborates the concept of increasing parathyroid activity following the treatment of hyperthyroidism.

Renal clearance of digoxin in man after sodium loading or furosemide treatment.

To evaluate the influence of different types of natriuresis on the renal clearance of digoxin (Cldig) and the Cldig/Clcr ratio, studies were performed in which sodium-depleted patients were placed on a moderately high sodium diet for 6 days. In another group natriuresis was evoked by furosemide. In the first study, in 10 patients, there was a 10-fold increase in Na excretion and a small rise in diuresis (V) and Clcr, which was accompanied by an increase in Cldig from 57.5 +/- 32, and 60.7 +/- 27.3 (duplicate measurements) to 103.9 +/- 55.4 (p less than 0.01) and 103.8 +/- 46.5 ml min-1 (p less than 0.01). Cldig/Clcr rose from 0.60 +/- 0.24 and 0.61 +/- 0.16 to 0.91 +/- 0.31 and 0.91 +/- 0.21, respectively (both p less than 0.005). Serum digoxin concentration declined from 1.24 +/- 0.35 and 1.19 +/- 0.40 to 1.02 +/- 0.35 and 0.97 +/- 0.32 micrograms/l (both p less than 0.01) during the high sodium diet. In the furosemide-induced natriuresis (6 patients), changes in Na excretion and V were a multiple of those caused by Na loading, but the Cldig/Clcr ratio was not increased. The results are in accordance with the concept of digoxin backdiffusion in the proximal tubules, which is dependent on proximal Na reabsorption. In the more distal segments of the nephron, where the action of furosemide occurs, there does not appear to be any transtubular movement of digoxin.

Propranolol increases arterial ammonia in liver cirrhosis.

Propranolol (20 mg 4 times a day) was given to patients with liver cirrhosis or fatty infiltration of the liver. In six patients with cirrhosis and a stable arterial plasma ammonia concentration before treatment, blood ammonia was increased significantly on day 3 of propranolol treatment. Arterial plasma ammonia concentration was still high on day 6 of propranolol. Individual percentage change in arterial ammonia ranged from 8% to 66%. After propranolol had been discontinued ammonia concentration returned to pretreatment concentrations in 3 to 6 days. In 3 patients with fatty livers and normal pretreatment ammonia concentrations no change was detected in arterial plasma ammonia while they were on propranolol.

Enhanced calcitonin release in chronic renal failure depending on the absence of severe secondary hyperparathyroidism.

In 27 patients with end-stage chronic renal failure an elevated calcitonin (CT) and parathyroid hormone was found. On stimulation with Ca i.v. there were 9 cases in whom delta CT proved to be higher than the maximal response of 50 pg ml-1 in controls. Supranormal CT responses were found predominantly in patients with normal alkaline phosphatase, who as a group increased their CT from 94.5 +/- 61 to 142.0 +/- 94 pg ml-1 (p less than 0.02). In contrast to this, patients with elevated alkaline phosphatase who also had a higher level of parathyroid hormone maintained unchanged CT on Ca stimulation. It is concluded that in chronic renal failure with severe secondary hyperparathyroidism, delta CT on stimulation is normal, while an enhanced delta CT often exists when hyperparathyroidism is of insufficient degree to cause a raised alkaline phosphatase.

Dissociation between changes in immunoreactive parathormone and its biological indices induced by cimetidine in primary hyperparathyroidism.

In three out of four patients with primary hyperparathyroidism, 2 000 mg of cimetidine daily caused a reduction of immunoreactive parathormone (iPTH) when measured at 8.30 and 11.30 on days 16 and 17 on treatment. Serum Ca, PO4 and maximal tubular reabsorption of PO4 remained unchanged. Excretion of cAMP/100 ml GFR remained elevated to at least the same extent as before treatment. Two patients, in whom cimetidine treatment was continued for an additional 4 weeks, did not show further hormonal or biochemical changes compared with the evaluation on days 16 and 17. We conclude that reduction of iPTH is not accompanied by any change in biological activity of this hormone. The reason for this discrepancy remains unclear.

Mammalian acetoacetate decarboxylase activity. Its distribution in subfractions of human albumin and occurrence in various tissues of the rat.

In this article further information is presented about the characteristics of the mammalian enzyme acetoacetate decarboxylase (acetoacetate carboxylase, EC 4.1.1.4). The Michaelis-Menten plot shows a sigmoidal relationship between the enzyme activity (v) and the substrate concentration (s) indicating an allosteric hindrance. Because of this, the KM value can only be predicted to be equal to or less than 1 X 10(-1) M. Cysteine and glutathione, although activating the spontaneous decarboxylation, have no effect upon the enzyme activity. From experiments with human albumin by means of gel filtration with Sephadex G-200, it can be concluded that the acetoacetate decarboxylase activity does not depend upon the degree of polymerisation of albumin. From experiments performed by means of ion exchange chromatography the enzyme activity may be localized in the non-mercaptalbumin fraction. Investigation of enzyme activity in homogenates of various rat tissues, as well as in their respective subfractions, reveals that: (1) the specific activity of brain tissue exceeds those of liver and kidney and (2) most of the activity in liver tissue is localized in the 20 000 X g supernatant, containing the endoplasmatic reticulum, the ribosomes and the soluble part of the cytoplasm, while in brain tissue a high activity is found in the nuclei fraction.

The syndrome of renal tubular acidosis with nerve deafness.

Two brothers with renal tubular acidosis and nerve deafness are described. Studies of the physiopathological characteristics of the renal acidification defect show that the defect is limited to the distal tubule. Renal tubular acidosis with nerve deafness is a distinct nosologic entity that is determined by an autosomal recessive trait.